Process for the preparation of a cyanobiphenyl

ABSTRACT

The subject-matter of the invention is a process for the preparation of o-(p-tolyl)benzonitrile, characterized in that an o-halobenzonitrile is treated with a p-tolylmagnesium halide in the presence of a manganous salt and of a cocatalyst comprising a transition metal.

THIS APPLICATION IS A 371 OF PCT/FR97/01577 FILED SEP. 8, 1997.

The present invention relates to a process for the preparation of acyanobiphenyl.

More particularly, the subject-matter of the invention is a process forthe preparation of o-(p-tolyl)benzonitrile of formula I

which constitutes the key intermediate in the synthesis of numerousactive principles of medicines acting in particular against hypertensionby a mechanism in which angiotensin II is inhibited.

o-(p-Tolyl)benzonitrile, hereinafter denoted more concisely asorthotolylbenzonitrile or OTBN, was disclosed for the first time in EP253,310 and a number of processes for its synthesis have recently beenprovided.

The process which seems to be the most appropriate for the preparationof OTBN is disclosed in EP 566,468 and consists of the reaction of ano-halobenzonitrile with a p-tolylmagnesium halide in the presence of amanganous salt, preferably MnCl₂. This method, with respect to thoseknown previously, has the advantage of taking place in a single stagewith yields of approximately 70% before crystallization. However, itgives 4,4′-dimethylbipohenyl, resulting from the condensation of thep-tolylmagnesium halide with itself, as reaction by-product.

It has now been found that, if the reaction between the p-tolylmagnesiumhalide and the o-halobenzonitrile is carried out in the presence of amanganous salt and of traces of a palladium(II) salt, the OTBN isobtained with a yield of at least approximately 92% while the4,4′-dimethylbiphenyl impurity falls below approximately 2.5%.

Thus, the subject-matter of the present invention is a process for thepreparation of o-(p-tolyl)benzonitrile, characterized in that ano-halobenzonitrile, preferably o-bromobenzonitrile, is treated with ap-tolylmagnesium halide in the presence of a manganous salt and of acocatalyst comprising a transition metal, preferably a palladium(II)salt.

The coupling reaction according to the invention is carried out in asolvent of the ether type, such as methyl t-butyl ether, dibutyl ether,dioxane or tetrahydrofuran, it being possible for the reactiontemperature to vary from −10 to 60° C., depending on the solventemployed.

This reaction results in the transient formation of a complex, which ishydrolysed according to known procedures, for example by means of anacid, such as hydrochloric acid.

As regards the manganous salt, it is preferably MnCl₂ or MnCl₄Li₂, itbeing possible for the latter to be formed in situ by addition of twomolar equivalents of LiCl and of one molar equivalent of MnCl₂.

This manganous salt takes part in the reaction in a proportion of 0.5 to1.3 molar equivalents per molar equivalent of startingo-halobenzonitrile.

The transition metal forming the cocatalyst is advantageously nickel,cobalt, platinum or, in particular, palladium.

Use is preferably made, as cocatalyst comprising a transition metal, ofa palladium(II) salt, in particular the nitrate, chloride, acetate,bromide, sulphate or the like, the chloride (PdCl₂) and the acetate(CH₃—COO—Pd—OOC—CH₃) being particularly advantageous. The palladium saltis preferably complexed, for example with at least one organophosphoruscompound comprising trivalent phosphorus. Mention may more particularlybe made of palladium complexes, such asbis(triphenylphosphine)-dichloro-, bis(tributylphosphine)dichloro-,bis(tri-cyclohexylphosphine)dichloro-,diallyltriphenyl-phosphinedichloro-,triphenylphosphinepiperidine-dichloro-, bis(cyclohexyloxime)dicarbonyl-,1,5,9-cyclododecatrienedichloro-, bis(triphenylphosphine)-dicarbonyl-,bis(triphenylphosphine) diacetate-, bis (triphenylphosphine) sulphate-or (2,4-pentanedione) -tetrakis(triphenylphosphine)palladium. Amongthese, palladium(II) complexes are particularly advantageous,1,3-bis(diphenylphosphino)propane (dppp) complexed with palladium(II)chloride or palladium(II) acetate being preferred.

The palladium salts and the organophosphorus compounds can be addedseparately to the reaction mixture.

In this case, the amount of organophosphorus compound is preferablysufficient to form the cocatalyst in situ in the form of a complex withthe palladium present. The said complex is generally prepared so thatthe P/Pd ratio is approximately 1/1, but such a ratio can vary between0.5/1 and 2/1 without having a significant detrimental effect on theresult of the process.

This cocatalyst is present in very small amounts in the reactionmixture, namely from 0.001 to 2 molar % per mole of startingo-halobenzonitrile.

According to a preferred procedure, the p-tolylmagnesium halide is inequimolar amounts or in slight excess (1 to 1.5 mol) with respect to theo-halobenzonitrile. In addition, the preferred manganous catalyst(MnCl₄Li₂) is formed either in situ, in equimolar amounts or in slightexcess (1 to 1.5 mol) with respect to the o-halobenzonitrile, or at thetime of use, before addition to the reaction mixture.

MnC:L₄Li₂ is prepared by reacting one equivalent of MnCl₂ with twoequivalents of LiCl.

The reaction can be carried out in tetrahydrofuran by adding, at atemperature of 10° C., the cocatalyst and the o-halobenzonitrile,optionally in solution in tetrahydrofuran, to a tetrahydrofuran solutioncomprising the p-tolylmagnesium halide and the manganous catalyst. Thisreaction, which is exothermic, can be controlled by adjusting the rateof addition of the substituted benzonitrile and of the cocatalyst, so asto maintain it below 35° C.

Alternatively, the reaction can also be carried out by adding thep-tolylmagnesium halide in, for example, tetrahydrofuran to a mixture ofo-halobenzonitrile, cocatalyst and manganous catalyst in, for example,tetrahydrofuran. In this case, the reaction temperature can be bettercontrolled and the addition of p-tolylmagnesium halide can be carriedout even at a higher temperature, about 50-55° C., so as to decrease theduration of the reaction and the amount of cocatalyst employed.

However, in order to improve the progress of the reaction, it can beadvantageous to add a cosolvent to the mixture comprising the manganouscatalyst. This cosolvent is preferably another ether or diether, forexample dimethoxyethane.

According to the above preferred procedure, hydrolysis is carried out insitu with hydrochloric acid and the OTBN thus formed is isolatedaccording to conventional techniques, for example by extraction with asuitable solvent, evaporation of the solvent and purification bycrystallization from ethanol or by chromatography.

The OTBN is thus obtained with very high yields, from 92 to 98%depending on the proportions of the reactants employed. It comprisesvery small amounts of 4,4′-dimethylbiphenyl, generally less than 2.5%.

The amount of 4,4′-dimethylbiphenyl which is formed according to theprocess of the present invention was compared with that which is formedaccording to the process disclosed in EP 566,468. Thus, by carrying outthe reaction:

according to EP 566,468, namely by using MnCl₂ alone as catalyst, in aseries of tests under the same conditions, the 4,4′-dimethylbiphenylby-product was obtained with a yield of 8 to 12% with respect to thep-tolylmagnesium bromide, i.e. 6.5 to 10% by weight of2-(p-tolyl)benzonitrile final product; according to the presentinvention, namely by using MnCl₂ end PdCl₂/dppp as catalyst andcocatalyst, in a series of tests under the same conditions, the4,4′-dimethylbiphenyl by-product was obtained with a yield of 0.5 to 1%with respect to the p-tolylmagnesium bromide, i.e. at most 0.65% byweight of final product.

The cocatalyst comprising a transition metal can also be a cobalt,nickel or platinum salt, as indicated above. In the case of a cocatalystcomprising nickel, use is generally made of a nickel(II) salt, such asnickel chloride or acetylacetonate. This salt is preferably complexedwith at least one organophosphorus compound comprising trivalentphosphorus, such as a phosphine, for example triphenylphosphine. Thenickel salt and the organophosphorus compound can be added separately tothe reaction mixture. This nickel-comprising cocatalyst isadvantageously pretreated with a reducing agent, such as a hydride, forexample dibutylaluminium hydride or diisobutylaluminium hydride, oralternatively with a methylmagnesium halide, for example methylmagnesiumchloride, so as to form catalysts comprising Ni(O), such asNi[P(C₆H₅)₃]₄. Systems comprising nickel acetylacetonate,triphenylphosphine and diisobutylaluminium hydride have proved to beparticularly advantageous.

The following non-limiting examples illustrate the invention. In theseexamples, the molar percentages of cocatalyst are calculated withrespect to the amount of ortho-halobenzonitrile.

EXAMPLE 1

MnCl₂ (0.65 g, 5.14 mmol) and LiCl (0.44 g, 10.28 mmol) are addedsuccessively, under a nitrogen atmosphere and at room temperature, to 2ml of anhydrous tetrahydrofuran. The mixture is stirred until the saltshave dissolved (formation of MnCl₄Li₂). A solution of p-tolylmagnesiumchloride in tetrahydrofuran (1.80N, 2.86 ml, 5.14 mmol) is then added sothat the temperature is maintained between −100° C. and 0° C.Dimethoxyethane (1 ml, 10.28 mmol) is then rapidly added at 0° C. andthe organomanganous compound thus obtained is kept stirring for 5 min at+100° C.

1/1: PdCl₂/dppp (0.023 g, 1 mol %) is added and then o-bromobenzonitrile(0.72 g, 3.955 mmol) is added. The temperature rises from +10 to +300°C. over 15 min and then slowly falls to +250° C. After stirring for 3hours at room temperature, the reaction mixture is hydrolysed using a 1Nhydrochloric acid solution (15 ml). After extracting with ethyl ether,the organic phase is dried over potassium carbonate, filtered and thenevaporated under vacuum. The oil thus formed is subsequently purified bychromatography (silica: 20 g; eluant: petroleum ether/ethylacetate=95/5). The o-(p-tolyl)benzonitrile thus obtained is thenharvested, with a yield of 96%, in the form of off-white crystals.

Melting point: +48° C.; ¹H NMR (CDCl₃) δ2.42 (s, 3H, CH₃); ¹³C NMR(CDCl₃) δ21.03, 110.85, 118.70, 127.09, 128.39, 129.22, 129.74, 132.60,133.47, 135.03, 138.43, 145.20.

EXAMPLES 2 and 3

By carrying out the preparation as described in Example 1, while using0.5 equivalents of MnCl₄Li₂ and 1.3 equivalents of p-tolylmagnesiumchloride per one equivalent of o-halobenzonitrile and while varying theamount of 1/1: PdCl₂/dppp, the o-(p-tolyl)benzonitrile yields shown inTable 1 were obtained.

TABLE 1 Stirring time 1/1 PdCl₂/dppp at room Yield of Example (molar %)temperature isolated product 2 1 90 minutes 95% 3 0.5 5 hours 92%

EXAMPLE 4

A suspension of MnCl₂ (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3.955 mmol)in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml ofdimethoxyethane (3.955 mmol) is stirred at room temperature. Afterstirring for approximately 30 minutes, a homogeneous medium is obtained.The addition is then so carried out of 1/1: PdCl₂/dppp (0.023 g, 1 mol%) and of o-bromobenzonitrile (0.72 g, 3.955 mmol) and then a solutionof p-tolylmagnesium chloride in tetrahydrofuran (1.80N, 2.86 ml, 5.14mmol) is added over 2 hours at room temperature. After stirring for 90minutes, the reaction mixture is treated as described in Example 1. Theo-(p-tolyl)benzonitrile is thus obtained with a yield of isolatedproduct of 95%.

EXAMPLE 5

The preparation is carried out exactly as described in Example 4, thePdcl₂/dppp complex being replaced by a 1:1 mixture of palladium(II)acetate and dppp. The o-(p-tolyl)benzonitrile is thus obtained with ayield of isolated product of 94%.

EXAMPLE 6

The preparation is carried out exactly as described in Example 4 but thePdCl₂/dppp complex is replaced with a 1:1 mixture PdCl₂2LiCl and dppp.The o-(p-tolyl)benzonitrile is thus obtained with a yield of isolatedproduct of 95%.

EXAMPLE 7

A suspension of MnCl₂ (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3.955 mmol)in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml ofdimethoxyethane (3.955 mol) is stirred at room temperature until, afterapproximately 30 minutes, a homogeneous medium is obtained. ThePdCl₂/dppp complex (0.0023 g, 0.1 mol %) and the o-bromobenzonitrile(0.72 g, 3 955 mmol) are then added and then a solution ofp-tolylmagnesium chloride in tetrahydrofuran (1.80N, 2.86 ml, 5.14 mmol)is added over 30 minutes. After stirring for 30 minutes, the reactionmixture is treated as described in Example 4. Theo-(p-tolyl)benzonitrile is thus obtained with a yield of isolatedproduct of 95%.

What is claimed is:
 1. Process for the preparation ofo-(p-tolyl)benzonitrile, wherein an o-halobenzonitrile is treated with ap-tolylmagnesium halide in the presence of (i) a manganous salt and (ii)of a cocatalyst comprising a transition metal.
 2. Process according toclaim 1, wherein the o-halobenzonitrile is o-bromobenzonitrile. 3.Process according to claim 1, wherein the manganous salt is MnCl₂ orMnCl₄Li₂.
 4. Process according to claim 1, wherein the cocatalystcomprising a transition metal is selected from the group consisting of apalladium salt, a cobalt salt, a nickel salt, and a platinum salt. 5.Process according to claim 1, wherein the cocatalyst comprising atransition metal is a palladium(II) salt.
 6. Process according to claim5, wherein the palladium(II) salt is a palladium(II) chloride orpalladium(II) acetate.
 7. Process according to claim 5, wherein thepalladium salt is added to the reaction mixture with an organophosphoruscompound comprising trivalent phosphorus.
 8. Process according to claim5, wherein the palladium(II) salt is in the form of a complex with anorganophosphorus compound comprising trivalent phosphorus.
 9. Processaccording to claim 8, wherein the palladium(II) salt is in the form of acomplex between, 1,3-bis(diphenylphosphino)propane and palladium(II)chloride or acetate.
 10. Process according to claim 4, wherein thenickel salt is nickel acetylacetonate.
 11. Process according to claim 4,wherein the nickel salt is added to the reaction mixture with anorganophosphorus compound comprising trivalent phosphorus.
 12. Processaccording to claim 4, wherein the nickel salt is in the form of acomplex with an organophosphorus compound comprising trivalentphosphorus.
 13. Process according to claim 4, wherein the nickel salt ispretreated with a reducing agent.
 14. Process according to claim 1,wherein the reaction is carried out in a solvent of the ether type. 15.Process according to claim 14, wherein the solvent is tetrahydrofuran.16. Process according to claim 1, wherein the reaction is carried out ina solvent of the ether type and a cosolvent of the diether type. 17.Process according to claim 16, wherein the solvent is tetrahydrofuranand the cosolvent is dimethoxyethane.